In Practice

Use and Safety of Unfractionated Heparin for Anticoagulation

During Maintenance Hemodialysis
Jenny I. Shen, MD, MS, and Wolfgang C. Winkelmayer, MD, ScD
Anticoagulation is essential to hemodialysis, and unfractionated heparin (UFH) is the most commonly used
anticoagulant in the United States. However, there is no universally accepted standard for its administration in
long-term hemodialysis. Dosage schedules vary and include weight-based protocols and low-dose protocols
for those at high risk of bleeding, as well as regional anticoagulation with heparin and heparin-coated dialyzers.
Adjustments are based largely on clinical signs of under- and overanticoagulation. Risks of UFH use include
bleeding, heparin-induced thrombocytopenia, hypertriglyceridemia, anaphylaxis, and possibly bone mineral
disease, hyperkalemia, and catheter-associated sepsis. Alternative anticoagulants include low-molecularweight heparin, direct thrombin inhibitors, heparinoids, and citrate. Anticoagulant-free hemodialysis and
peritoneal dialysis also are potential substitutes. However, some of these alternative treatments are not as
available as or are more costly than UFH, are dependent on country and health care system, and present
dosing challenges. When properly monitored, UFH is a relatively safe and economical choice for anticoagulation in long-term hemodialysis for most patients.
Am J Kidney Dis. 60(3):473-486. 2012 by the National Kidney Foundation, Inc.
INDEX WORDS: Heparin; hemodialysis; anticoagulation; complications; bleeding.

CASE PRESENTATION

INTRODUCTION

A 50-year-old man with a history of diabetes mellitus and end-stage

renal disease (ESRD) became hypotensive 15 minutes into his dialysis session. He had been receiving maintenance hemodialysis through
a left arteriovenous fistula 3 times a week for the past 5 years without
complication. Per the dialysis unit protocol, the nurses had been
administering a bolus of 2,000 IU of heparin at the start of every
session, followed by a maintenance infusion of 1,000 IU/h. He does
not have a history of a bleeding disorder, but takes 81 mg of aspirin
daily. His blood pressure was 142/84 mm Hg at the start of the session,
but decreased acutely to 74/54 mm Hg in the first 15 minutes of the
session. He denied shortness of breath, chest pain, and subjective
fevers or chills, but noted some mild abdominal discomfort and
lightheadedness. On physical examination, his temperature was 97F,
pulse was 90 beats/min, blood pressure was 74/54 mm Hg, and
respiratory rate was 18 breaths/min. Cardiac and respiratory examination findings were unremarkable, but his abdomen was diffusely
tender to palpation. The patients blood pressure improved to 85/62
mm Hg after a 250-mL bolus of saline solution. However, his
abdominal pain worsened, so the hemodialysis treatment was discontinued and he was sent to the emergency department for further
evaluation.
Laboratory measurements obtained in the emergency department
were significant for a white blood cell count of 18,000 cells/L,
platelet count of 400,000/L, and hemoglobin level of 9 g/dL. A week
earlier, his hemoglobin level had been 11 g/dL. An electrocardiogram
was normal, and troponin levels were negative. However, a computed
tomographic scan of the abdomen showed a perforated colon secondary to ischemic bowel with substantial gastrointestinal (GI) bleeding,
for which he underwent an emergent hemicolectomy. His hospital
course was complicated by continued bleeding; by the time of
discharge 10 days later, he had been transfused a total of 8 units of
packed red blood cells and his hemoglobin level had stabilized at 9.5
g/dL. His platelet levels never decreased, and an enzyme-linked
immunosorbent assay was negative for heparin-induced antibodies.
The patient underwent anticoagulant-free hemodialysis acutely.
After discharge, he was instructed to avoid taking aspirin. Given
the recent hospitalization for a major bleeding event, his primary
nephrologist was asked to review the patients anticoagulation for
long-term hemodialysis.

Hemodialysis is a life-saving procedure currently

used by more than 1.4 million patients with ESRD
worldwide.1 Although hemodialysis first developed in
the 1920s, early use was complicated by clotting of
the dialysis circuit.2 It was not until the 1940s, with
the introduction of heparin to anticoagulate the circuit, that hemodialysis became feasible for a large
population.3 Since then, unfractionated heparin (UFH)
has continued to be the most commonly used anticoagulant in the United States due to its availability,
affordability, and short half-life.4,5
UFH has several potential risks, primarily bleeding.
Hemodialysis patients already have an increased tendency to bleed due to the build up of uremic toxins
that cause platelet dysfunction.6-10 Paradoxically, they
also have an increased risk of clotting, stemming from
endothelial damage and perturbations in the metabolism, expression, and activity of certain procoagulant
factors.11 In a prospective cohort study of patients
with atrial fibrillation, those with estimated glomerular filtration rate 30 mL/min/1.73 m2 had a 39%
greater risk of thromboembolism compared with those

Am J Kidney Dis. 2012;60(3):473-486

From the Division of Nephrology, Stanford University School of

Medicine, Palo Alto, CA.
Received July 18, 2011. Accepted in revised form March 30,
2012. Originally published online May 7, 2012.
Address correspondence to Jenny I. Shen, MD, MS, Division of
Nephrology, Stanford University School of Medicine, 780 Welch
Rd, Ste 106, Palo Alto, CA 94305. E-mail: jishen@stanford.edu
2012 by the National Kidney Foundation, Inc.
0272-6386/$36.00
http://dx.doi.org/10.1053/j.ajkd.2012.03.017
473

Shen and Winkelmayer

Intrinsic Pathway

Extrinsic Pathway

XII

Leukocyte
ac
va
on

Dialyzer membrane

Surface damage

Tissue factor

XIIa

VIIa
VIIIa

XI

VII

VIII

XIa
UFH
IX

IXa
Ca2+
Heparinoids
X

Xa
LMWH

Ca2+
V

XIII

Va

DTI

Ca2+
Prothrombin

XIIIa

Thrombin
Ca2+

Citrate
Fibrinogen

Fibrin

Fibrin clot

Figure 1. Coagulation cascade. The dialyzer membrane activates the coagulation cascade primarily through the activation of
leukocytes, which release tissue factor, triggering the extrinsic pathway. Exposure of the membrane to factor XII may also play a
procoagulant role. Unfractionated heparin (UFH) binds to antithrombin, which then inhibits both factor Xa and thrombin, halting
the coagulation cascade. Low-molecular-weight heparin (LMWH) primarily acts by inhibiting factor Xa because it generally is too
short to link antithrombin and thrombin. Direct thrombin inhibitors (DTIs), as the name implies, stop the cascade by inhibiting
thrombin. Heparinoids, similar to LMWH, inhibit factor Xa. Citrate stops coagulation by binding calcium (Ca2).17

with estimated glomerular filtration rate 60 mL/min/

1.73 m2.12 Clinicians may prescribe anticoagulants to
prevent such thromboembolic events, but the medications often exacerbate the bleeding risk. Holden et
al10 estimated the incidence rate of major bleeding
events in hemodialysis patients to be 3.1-6.3 events/
100 person-years, depending on the use of warfarin
and aspirin. Phelan et al13 calculated an even higher
incidence rate of 10.8 major bleeding events per 100
person-years in hemodialysis patients receiving warfarin, which was significantly higher than the rate of 2.1
in nondialysis-dependent warfarin users. Three large
studies of dialysis patients with atrial fibrillation have
found a more than doubling of hemorrhagic stroke in
users of warfarin, whereas the association with ischemic stroke was inconsistent.9,14,15 With increasing
interest in prolonged dialysis regimens such as daily
and nocturnal dialysis, the relative minority of patients receiving these are being exposed to more
heparin, which may further increase bleeding events
and other complications.
Despite the potential risks, little is known about the
safety of using UFH for hemodialysis. Furthermore,
although guidelines exist for heparin use in other
clinical conditions such as pulmonary embolism, there
474

is no American standard for heparin dosage in longterm intermittent hemodialysis.16 This article reviews
the use and safety of UFH as anticoagulation for
long-term intermittent hemodialysis and briefly discusses its alternatives.

PHARMACOLOGY
UFH is a sulfate polysaccharide that includes a
component that binds and activates antithrombin,
inhibiting thrombin and factor Xa and thus stopping
the coagulation cascade and promoting anticoagulation (Fig 1).17 UFH activity can be monitored by
measuring the activated partial thromboplastin time
(aPTT), or the time it takes for a clot to form when
treated with an activator and calcium. The half-life
of UFH is about 1 hour in patients with kidney
failure (vs 30 minutes in patients with normal
kidney function), but other facets of hemodialysis,
including dialyzer type and dose of erythropoietin,
also can affect its activity.4,18-23
PREPARATION
Although most UFH currently is produced from
porcine mucosa, heparin derived from bovine tissue is
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Heparin During Maintenance Hemodialysis

Table 1. Sample Dosing Schedules for UFH for Anticoagulation During Long-term Hemodialysis
Loading Dose

Maintenance Infusion

Parameters for Adjustment

Standard Protocols
25 IU/kg

2,000 IU

1,000 IU/h
Stop 30-60 min before end of treatment
None

If excessive bleeding or clotting occurs, adjust

maintenance infusion by 500 IU/h
If excessive bleeding or clotting occurs, adjust loading
dose by 500 IU
If clotting persists with loading dose 4,500 IU, add
second bolus dose or start maintenance infusion

Low-Dose Protocols
10 IU/kg

25 IU/kg

10 IU/kg/h
Stop 30-60 min before end of treatment

None

If excessive bleeding occurs, eliminate loading dose

If bleeding persists or clotting occurs, adjust
maintenance infusion by 500 IU/h
If excessive bleeding occurs, decrease loading dose by
5 IU/kg
If clotting occurs, add second bolus dose (50% of first
bolus) or start maintenance infusion

Note: The authors recommend the first protocol for all patients. Alternative protocols from the literature are listed; there is no evidence
favoring one protocol over another. Standard protocols are appropriate for most patients. Low-dose protocols have been suggested for
patients with an increased risk of bleeding.16,28,29
Abbreviation: UFH, unfractionated heparin.

still available. Interestingly, the source of the drug can

influence its effects.24 Bovine heparin causes the
same amount of bleeding, but has half the anticoagulant effect of porcine heparin. However, they are sold
as equivalent drugs. One study attributed a spike in
bleeding complications in Brazil to an increase in the
use of bovine versus porcine heparin.24 In the United
States, the Food and Drug Administration (FDA)
restricts the source of heparin to porcine material out
of concern that bovine sources may be contaminated
with mad-cow disease.25 However, porcine heparin
may carry a greater risk of anaphylaxis (see Complications).
Manufacturing standards of all types of heparin
came under greater scrutiny in 2008 when a string of
adverse reactions in dialysis facilities, including 80
deaths, was linked to contamination of heparin by
oversulfated chondroitin sulfate, which was used to
lower the cost of production.26,27 Patients reported
hypotension, nausea, and shortness of breath within
30 minutes of receiving heparin. The source of the
contamination was traced to a single distributor, and
multiple batches of heparin were recalled. Since then,
the FDA has identified 22 Chinese factories that
supplied contaminated heparin and prevented them
from importing further products to the United States.
Additionally, the FDA now recommends that distributors test every batch of heparin for oversulfated chondroitin sulfate.25

DOSING SCHEDULES
Currently, there is no American standard for heparin dosage in long-term intermittent hemodialysis.16
Am J Kidney Dis. 2012;60(3):473-486

Instead, dialysis units use a variety of empirically

based protocols (Table 1). In general, patients receive
a bolus of 2,000-4,000 IU at the start of the dialysis
treatment.28 A continuous or hourly intermittent infusion often follows, which provides more consistent
levels of anticoagulation (and presumably less risk of
bleeding) than a single second bolus.4,30 The hourly
rate can range from 500-2,000 IU/h or more, depending on the dose of the initial bolus, and some centers
avoid all heparin in the final hour of dialysis to
decrease the likelihood of bleeding at the needle
sites.4,31 Many dialysis units use weight-based dosing
protocols, but interpatient variability in heparin elimination makes these protocols only marginally better at
achieving consistent levels of anticoagulation than
fixed doses, except at the extremes of weight.31-34
Given the variability in heparin activity, some
sources advocate dosing heparin to reach a goal aPTT
of 1.5 times the predialysis aPTT instead of relying on
fixed or weight-based doses.16,31-34 This approach has
been shown to improve dialysis adequacy and increase the number of reuses of a single dialyzer.
However, this method involves complicated equations
and the need for repeated laboratory tests, which leads
to high costs, increased technician time to collect and
process the samples, and potential exacerbation of
anemia through repeated blood draws.30,32,33,35-37
Instead of formal laboratory measurements, most
American dialysis units monitor their patients clinically for signs of under- and overanticoagulation.
Visual clots in the circuit and increased postpump
arterial pressure are signs of insufficient anticoagulation, whereas extended time needed to achieve hemo475

Shen and Winkelmayer

stasis at the end of the dialysis treatment is the

primary sign of overanticoagulation.16 However, dialysis-specific factors, such as low blood flow, high
hematocrit, high ultrafiltration rate, vascular access
stenosis, and poor needle placement, can contribute to
both clotting and bleeding. Thus, clinical assessment
is useful for identifying coagulation problems during
dialysis, but it cannot reliably predict the risk of
bleeding after dialysis.
In contrast to the United States, Europe has published guidelines for heparin administration in longterm hemodialysis, as outlined in the European Best
Practices Guidelines: UFH at 50 IU/kg as an initial
bolus, then 800-1,500 IU per hour of dialysis.38 However, it is unclear whether implementation of this
protocol has decreased the complication rate of heparin use in Europe.
In general, in light of the high risk of possibly
devastating bleeding complications in patients undergoing hemodialysis, we believe that a responsible
clinical approach is to use the smallest dose necessary
to complete the hemodialysis session without clotting
of the circuit. This may require an ongoing titration
process. For patients with a standard dialysis session
of about 4 hours, we recommend an initial bolus of 25
IU/kg followed by a continuous infusion of 1,000
IU/h, to be stopped 30-60 minutes before the end of
the session (Table 1). If the patient routinely requires
more than 15 minutes to clot at the needle puncture
sites despite proper needle insertion technique, the
maintenance UFH infusion dose should be decreased
by 500 IU/h and eventually may be eliminated if the
prolonged bleeding after removal of the needle does
not improve with reduced maintenance UFH dose.
(Of course, other reasons for prolonged bleeding such
as outflow stenosis should be ruled out.) Conversely,
if the extracorporeal circuit clots during the run and
the practitioner has ruled out vascular access and
dialyzer equipment as the causes, the rate of UFH
infusion should be increased by 500 IU/h.

REGIONAL ANTICOAGULATION WITH HEPARIN,

HEPARIN-COATED DIALYZERS, AND
LOW-DOSE HEPARIN
Hemodialysis patients with an even higher risk of
bleeding, such as postoperative patients or those with
a recent history of a bleeding event, should receive
reduced doses of heparin. Regional anticoagulation
with heparin, special dialyzers, and low-dose heparin
protocols have been used in these situations.
In regional anticoagulation with heparin, heparin is
added before the blood enters the dialysis circuit, but
is reversed by protamine, which is infused prior to the
blood returning to the patient.39 This theoretically
prevents exposure of the patient to active heparin.
476

However, the practice has fallen out of favor due to

the complexity of the protamine infusion and the
rebound anticoagulation resulting from latent detachment of the protamine from heparin in the patients
body.40,41
Manufacturers also have developed special membranes, such as the AN69 ST membrane, that are
coated with a substance that binds heparin.42 Technicians must rinse the system with heparinized saline
before dialysis, but either no or only a low level of
heparin is needed during dialysis.18,42-44 Given this
complexity, the increased cost of the special membranes, the fact that patients are still exposed to a
small amount of heparin, and clotting rates that can be
as high as 39%, these dialyzers generally have not
been as popular as use of the simpler low-dose heparin protocols.
The most practical approach is a low-dose heparin
protocol, which is easier to use and more effective
than regional anticoagulation with heparin and coated
membranes.45 However, similar to regular heparin
dosing, there is no standard scale.16,46 Generally,
patients receive about half the full dose of heparin as a
bolus of 10-25 IU/kg, followed by a maintenance
infusion of 10 IU/kg/h (Table 1).16,28,29 Our recommendation is to use the same protocol we suggested
previously for all patients (a loading dose of 25 IU/kg,
followed by a maintenance infusion of 1,000 IU/h to
be stopped 30-60 minutes before the end of the
session) because it already delivers a low dose of
heparin when appropriately titrated, obviating the
need for an explicit low-dose regimen.

COMPLICATIONS OF UFH USE

The benefits of UFHlow cost, availability, short
half-life, and reversibilitymust be weighed against
its risks. There are several known complications of
UFH use with varying degrees of impact on the
hemodialysis population (Box 1).
Bleeding
Because heparin is an anticoagulant, its chief complication is bleeding. Although there are many cases
of bleeding in patients receiving heparin with longterm hemodialysis, few large-scale studies have proved
that heparin increases bleeding risk in this population.
GI Bleeding

Although one of the most common major bleeding

events in hemodialysis patients is GI bleeding, no
well-conducted study has shown that heparin increases the risk of GI bleeding.
Wasse et al47 studied a cohort of dialysis patients
from the US Renal Data System Morbidity and Mortality Studies to identify risk factors for first hospitalAm J Kidney Dis. 2012;60(3):473-486

Heparin During Maintenance Hemodialysis

Box 1. Risks and Benefits of UFH for Anticoagulation During
Long-term Hemodialysis
Risks

Bleeding
Heparin-induced thrombocytopenia
Hypertriglyceridemia
Anaphylaxis
Hyperkalemiaa
Bone mineral diseasea
Catheter-related sepsis

Benefits

Decreased clotting of the dialysis circuit

Low cost
Widely available
Staff familiarity with use
Short half-life
Reversible with protamine
Abbreviation: UFH, unfractionated heparin.
Established in nondialysis populations.

ization for upper-GI bleeding. Although heparin use

was not analyzed separately, the use of any antiplatelet or anticoagulant medication at baseline was not
associated with increased risk of upper-GI bleeding.
The study is limited by the possibility of confounding
by indication; patients prone to bleeding may have
been less likely to be prescribed antiplatelet or anticoagulant medications. Still, the null finding was striking given the size of the cohort.
Chacati and Godon48 conducted an autopsy study
of 94 patients with ESRD (75 had been receiving
hemodialysis) and 258 controls without ESRD. They
assumed that every hemodialysis patient received
heparin with dialysis. The prevalence of upper-GI
bleeding was lower in patients who had survived
hemodialysis for more than a month compared with
those who had died before or during the first month of
hemodialysis (31% vs 58% and 57%, respectively)
and was virtually the same as the control group
(35%). This suggests that after the first month, hemodialysis may reverse some of the metabolic derangements that predispose patients with ESRD to GI
bleeding and may indicate that heparin does not
necessarily confer an increased risk of bleeding in this
population.
Winkelmayer et al15 found no difference in GI
bleeding rates between dialysis patients with new
atrial fibrillation who received warfarin compared
with similar patients who did not receive this drug.
Recently, Yang et al49 reported that the trend in
acute nonvariceal upper-GI bleeding in dialysis patients did not decrease from 1998 to 2007 despite a
contemporary decrease in GI bleeding in the nondialysis population. They speculate that increased use of
antiplatelet or anticoagulant medications over time, in
part driven by the increased use of hemodialysis
Am J Kidney Dis. 2012;60(3):473-486

versus peritoneal dialysis, may have attributed to this

effect. However, they did not have medication information in their data set to test this hypothesis. Also,
other characteristics of the dialysis population that
have changed over time may be driving the trend,
including older age and greater prevalence of comorbid conditions.
Cerebral Hemorrhage

Cerebral hemorrhage is a life-threatening complication highly associated with kidney failure. Some speculate that it was the cause of death of musician Wolfgang Amadeus Mozart, who many believe had kidney
failure.50 The relative risk of cerebral hemorrhage in
incident dialysis patients compared with the general
population is 5.4.51 However, the few data available
suggest that heparin does not contribute to this risk.
A recent study found the incidence of cerebral
hemorrhage in Japanese long-term hemodialysis patients to be 8.7 events/1,000 patient years.52 However,
there was no difference in the dose of heparin given to
those who had the event and those who did not or
between those who died of their hemorrhage and
those who survived. Furthermore, 85% of the patients
had their event more than 6 hours after the end of their
hemodialysis session. The half-life of heparin is about
1 hour, making heparin an unlikely contributor to
cerebral hemorrhage in this group. Moreover, there
was no difference in the size of hematomas based on
the time of the cerebral hemorrhage from the last
hemodialysis session, again suggesting that heparin
did not have a role in its exacerbation.
A similar cohort study of Japanese long-term dialysis patients found that cerebral hemorrhage occurred
on average 35.5 hours after the last hemodialysis
session, implying that heparin has a minimal, if any,
role in the cause.53
Other Bleeding Events

Data for the incidence of retroperitoneal hemorrhage in hemodialysis patients are limited to case
series from the 1970s.54-56 All reported patients were
receiving heparin with hemodialysis at the time of
their event. Milutinovich et al57 performed the most
detailed study, a case series of 6 hemodialysis patients, 4 of whom were also on warfarin therapy. The
average serum urea nitrogen level was 80 mg/dL;
therefore, uremia likely had a limited role in the
bleeding. Also, all the events happened during dialysis, during exposure to heparin. Still, the cases are too
few to provide a convincing causal relationship between heparin and the bleeding.
Hemodialysis patients are at risk of ophthalmologic
bleeding given their high rate of diabetes and hypertension. A series of 66 hemodialysis patients with prolif477

Shen and Winkelmayer

erative diabetic retinopathy who received heparin

with dialysis had no increased bleeding complications
with vitrectomy compared with reported rates in similar studies in patients with diabetes not on dialysis
therapy.58 Another study cited a patient with a spontaneous hyphema who had recently received 10,000 IU
of heparin with dialysis, but a subsequent 66 hemodialysis patients who received the same dose or more
heparin did not have such a complication.59 Again, the
data are limited, but heparin does not appear to
increase ophthalmologic bleeding.
Various other bleeding events have been speculated
to be related to heparin given during hemodialysis.
Galen et al60 reported a case of a pleural effusion
converting to a hemorrhagic effusion after starting
hemodialysis with heparin. In a case series of 12
patients with ESRD with hemopericardium from the
1960s, 3 worsened in the immediate postdialysis period; this may be the root of the warning against the
use of heparin in patients with uremic pericarditis.61
However, no larger patterns between these types of
bleeding events and heparin have been shown since.
Heparin-Induced Thrombocytopenia
One of the most serious side effects of heparin is
heparin-induced thrombocytopenia (HIT). We pro-

vide a brief overview of the syndrome here; for a

more in-depth review, we direct readers to a previous
article from Davenport62 in the American Journal of
Kidney Diseases In Practice series.
Two types of HIT exist.63 In the milder form, type I
HIT, heparin binds, activates, and depletes platelets.
This typically occurs within the first 4 days of starting
heparin therapy and thus is seen in incident hemodialysis patients.64 The thrombocytopenia is mild, with
average platelet levels of 100 109 per 1 L of blood,
and typically resolves with time. No antibodies are
formed, and heparin therapy does not need to be
stopped.
In the more severe potentially life-threatening form,
type II HIT, heparin exposure induces both bleeding
and thromboembolic complications.62 Heparin binds
to platelets, releasing platelet factor 4 (PF4), which in
turn binds heparin (Fig 2). Antibodies then can bind to
the heparin-PF4 complex, causing a cascade of more
platelet aggregation that leads to severe thrombocytopenia (platelets 50 109 per 1 L of blood) and
subsequent bleeding complications. The binding of
these heparin-induced antibodies to endothelial cells
also can cause paradoxical thrombus formation with
subsequent limb-threatening ischemia and even fatal
pulmonary emboli. Type II HIT usually occurs 5-12

Figure 2. Mechanism of thrombosis

in heparin-induced thrombocytopenia.
Several mechanisms contribute to thrombosis in heparin-induced thrombocytopenia. Platelet factor 4 heparinimmunoglobulin G (IgG) complexes bind to the
Fcg receptor IIA on platelets, leading to
platelet aggregation, acceleration of
soluble clotting reactions (such as the
conversion of factor II [prothrombin] to
factor IIa [thrombin]), and activation of
neighboring endothelial cells. IgG antibodies bind to heparinplatelet factor 4
complexes on the surface of endothelial
cells, leading to additional endothelialcell activation. Endothelial-cell activation
in turn may lead to focal changes in the
expression of endothelial-derived procoagulants and anticoagulants. Finally,
platelet microparticles, which may be increased in heparin-induced thrombocytopenia, have increased procoagulant activity. Reproduced from Aird and Mark65
with the permission of the Massachusetts
Medical Society.
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Heparin During Maintenance Hemodialysis

days after heparin exposure, but can happen immediately in the case of re-exposure.66 All forms of heparin, including low-molecular-weight formulations,
must be discontinued at once, and the current recommendation is to avoid future heparin exposure.62,67
Additionally, patients should undergo systemic anticoagulation with a nonheparin agent, such as lepirudin,
argatroban, or danaparoid, for at least 2-3 months to
prevent thrombotic complications.67
The reported prevalence of HIT in long-term hemodialysis patients ranges from 0.26%-3.9%.68-70 Complications of the syndrome vary in severity and frequency in this population. Clotting of the dialysis
circuit is a common, but generally benign, complication.69,71 In one single-center study, vascular access
thrombosis occurred in 40% of patients with HIT.72 In
contrast, in a national survey of HIT in the hemodialysis population in the United Kingdom, serious complications occurred less frequently: only 8% had a deep
vein thrombosis, 4% experienced a pulmonary embolism, and 4% experienced a retroperitoneal hemorrhage.68 Other rare complications include case reports
of skin necrosis and pseudo-pulmonary embolism.73-76
The diagnosis of HIT must be made based on both
clinical criteria and laboratory testing. Because the
differential diagnosis for thrombocytopenia is extensive in chronically ill dialysis patients, the 4T scoring
system can be used to calculate the probability that a
patient has HIT based on the severity of thrombocytopenia, timing of the decrease in platelets, presence of
thrombosis or other acute systemic symptoms, and
absence of other causes of thrombocytopenia.77 This
score aids in the interpretation of laboratory results,
which have varying levels of sensitivity and specificity.78 Although immunoassays are widely available
and have sensitivities ranging from 80%-100%, their
specificity can be as low as 50%. However, the
serotonin release assay, a functional test that detects
platelet activation when exposed to both heparin and
the patients serum, is 95% sensitive and specific but
not commonly available. Even a combination of functional and immunoassays can have specificity as low
as 80% when clinical events are not taken into account. Thus, it is important that the diagnosis be
supported both clinically and by laboratory results
because the treatment, systemic anticoagulation, is
not without risk.
Recently, several studies have demonstrated that
simply having heparin-induced antibodies, even without thrombocytopenia, is still associated with a 2- to
7-fold increase in morbidity and mortality in hemodialysis patients.72,79-83 The prevalence of heparininduced antibodies is as high as 17% in hemodialysis
patients; therefore, this is a potentially major determinant of outcome in this population.
Am J Kidney Dis. 2012;60(3):473-486

Heparin is necessary for the development of heparininduced antibodies and HIT, but there has been no
documentation of a dose-dependent response. In a
Japanese study of incident hemodialysis patients, the
dose of heparin for those who developed HIT was not
significantly different from patients without HIT.69
This leaves little motivation to decrease the dose of
heparin used with hemodialysis without further research.
Hypertriglyceridemia
Heparin is known to cause hypertriglyceridemia,
likely through the depletion of lipoprotein lipase (LPL),
the enzyme that breaks down triglycerides.84 LPL
normally is bound to the vascular endothelium, but a
bolus of heparin will release LPL into the free circulation. This transiently increases LPL activity, but ultimately depletes its stores, leading to a build-up of
triglycerides. Hypertriglyceridemia contributes to atherosclerosis, a leading cause of death in hemodialysis
patients, making this a potentially significant side
effect of heparin. However, to date, no study has
shown that a decrease in triglyceride levels leads to
lower morbidity or mortality in this population.
No study has compared triglyceride levels of longterm hemodialysis patients receiving heparin with
those of patients receiving heparin-free treatment.
However, a number of crossover studies have compared low-molecular-weight heparin (LMWH) to UFH
in long-term hemodialysis and its effect on triglycerides because LMWH is believed to deplete LPL less
than UFH.85 Most found that triglyceride levels were
decreased by as much as 34% when patients switched
to LMWH and rebounded when they reverted to UFH;
2 studies found no difference.6,48,86-91
Anaphylaxis
Anaphylaxis is a risk of any drug, including heparin. Although a recent outbreak of allergic-type reactions to UFH that occurred in 2008 has been traced to
contamination of the heparin with oversulfated chondroitin sulfate, there was a case of a 77-year-old
woman with anaphylaxis that predated the period of
contaminated heparin.26 She experienced vomiting,
tachypnea, rales, hypoxia, and thrombocytopenia at
the start of the hemodialysis treatment with both UFH
and LMWH.92 Changes in the dialysis filter did not
resolve the symptoms, but replacing heparin with
hirudin as the anticoagulant did. Anaphylaxis to UFH
in nondialysis patients also has been linked to allergies to porcine products, with at least one case resolving after replacement with bovine heparin.93,94 Hypotension, dyspnea, angioedema, urticaria, tachycardia,
and diaphoresis are other signs and symptoms of
heparin anaphylaxis that may be mistaken for dialyzer
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Shen and Winkelmayer

reactions; it is important for clinicians to consider

heparin sensitivity in the differential diagnosis of
acute hemodialysis-related complications. Close monitoring of patients during their initial hemodialysis
session is crucial to catching such life-threatening
events early.
Bone Mineral Disease
UFH is known to increase the risk of osteoporosis
in pregnancy, but limited studies have been done in
the hemodialysis population.95 Binici and Gunes96
found no association between heparin use and reduced bone mineral density in hemodialysis patients
with metabolic syndrome. Lai et al97 found that bone
mineral density was lower in a cohort of 40 stable
hemodialysis patients treated with heparin than in
age-matched controls without either kidney disease or
heparin use, but this was confounded because bone
mineral metabolism is deranged in all patients with
kidney failure. The role of heparin in bone mineral
disease remains unclear in hemodialysis patients.
Hyperkalemia
Hypoaldosteronism with resultant hyperkalemia is
a known side effect of UFH.98 Heparin decreases
aldosterone by decreasing both the number and sensitivity of angiotensin II receptors on adrenal zona
glomerulosa cells. No studies have examined the
difference in potassium levels between long-term hemodialysis patients who do and do not receive heparin, likely because hemodialysis patients commonly
are hyperkalemic as a consequence of their kidney
failure. Moreover, given the low glomerular filtration
rates in this population, the renal effect of aldosterone
is at best attenuated. In a crossover study of 11
long-term hemodialysis patients, Hottelart et al92 found
that predialysis potassium levels decreased from 5.66
mEq/L to 5.15 mEq/L when patients were given
LMWH instead of UFH. This mild decrease could
have been due to changes in diet, which were not
monitored by the study. Importantly, the dialysate
potassium concentration can be changed to address
any hyperkalemia that may be associated with heparin, making this a less clinically significant side effect
for hemodialysis patients.
Catheter-Related Sepsis
One study has investigated the association between
systemic heparin use in hemodialysis patients with
catheter-related sepsis.99 In a study published in 2005,
heparin was shown to facilitate the creation of biofilm, sheets of bacteria that adhere to the surfaces of
devices like catheters, so it potentially can increase
the rate of infection.100 In that study, 559 long-term
hemodialysis patients using catheters were followed
480

up during a 6-year period. A Cox proportional hazards

analysis found that a bolus of UFH midtreatment (but
not loading bolus or total UFH dose) was a risk factor
for catheter-related sepsis. The authors hypothesize
that given the lack of association between infection
and total heparin dose, the second bolus may have
increased the risk of infection through increased opportunity for contamination of the dialysis circuit, not
through promotion of biofilm formation.

ALTERNATIVES TO UFH
Given the limitations of UFH, various alternative
anticoagulants have been used in long-term hemodialysis (Table 2). Although they have advantages over
UFH, most are prohibitively expensive for wide use,
although prices and availability vary by country and
health care system.
Low-Molecular-Weight Heparin
An alternative to UFH is LMWH. A heparin unit
must be at least 18 saccharide units in length or have a
molecular weight of 5,400 Da to link antithrombin
and thrombin. LMWH, which has an average molecular weight of 4,500-5,000 Da, usually is too short to
bind the 2 proteins; instead, LMWH primarily acts by
inhibiting factor Xa (Fig 1).17
LMWH is recommended over UFH as anticoagulation in the European Best Practice Guidelines for
Hemodialysis.38 Several qualities make it more attractive than UFH. It is easier to dose by weight because it
has less nonspecific binding than UFH.101 Its short
length also makes it more difficult to form the complex of heparin, PF4, and antibodies that cause HIT.102
As noted, several studies have shown that patients
lipid profiles improve when switched from UFH to
LMWH. Limited data suggest that LMWH also might
have fewer bone side effects than UFH.97 LMWH is
renally cleared, leading to an increased half-life in
patients with ESRD, and protamine cannot reliably
reverse its effects; thus, it may theoretically increase
bleeding risks. However, a meta-analysis of 11 trials
found no increased risk of bleeding compared with
UFH when it is used for anticoagulation in long-term
hemodialysis.103,104
Various LMWH products are used in Europe, where
decreasing prices have made them an economically
feasible alternative to UFH.105 They include dalteparin, enoxaparin, nadroparin, reviparin, and tinzaparin. In common practice, doses are adjusted according to clinical parameters, such as clotting of the
extracorporeal circuit, and most are effective when
given as a single bolus dose at the start of a standard
4-hour session.38,105 Although manufacturers recommend doses on their package insert, most of the
LMWHs are effective at preventing clotting of the
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Heparin During Maintenance Hemodialysis

Table 2. Alternatives to UFH for Anticoagulation During Long-term Hemodialysis
Method

Low-molecular-weight heparin

Drawbacks

Direct thrombin inhibitors

Heparinoids

Regional citrate anticoagulation

Anticoagulant-free
hemodialysis

Peritoneal dialysis

Benefits

Cost
Prolonged half-life
No reversal agent
Cost
Argatroban not safe in hepatic
impairment
Hirudin and derivatives have prolonged
half-life
No reversal agent
Cost
Prolonged half-life
No reversal agent
Possibility of cross-reaction with HIT
antibodies
Cost
Labor (frequent monitoring of calcium
levels, complicated setup of circuit)
Risk of hypernatremia, alkalosis, and
hypocalcemia if poorly monitored
Cost (due to increased changing of
dialyzer)
Labor (frequent monitoring and flushing
of the extracorporeal circuit)
Difficulty achieving goal ultrafiltration
Not appropriate for patients who are not
independent or with poor social support
Not appropriate for patients with
medical contraindications

Easier to dose
Less hypertriglyceridemia

Can be used in patients with history of HITa

Can be used in patients with history of HITa

Can be used in patients with history of HITa

Low risk of bleeding

Can be used in patients with history of HITa

Lowest risk of bleeding

Can be used in patients with history of HITa

Lower cost

Abbreviations: HIT, heparin-induced thrombocytopenia; UFH, unfractionated heparin.

a
Note that these agents should be used in conjunction with a systemic nonheparin anticoagulant in the first few months after the
diagnosis.

circuit even at reduced doses, an important consideration for patients who are at greater risks of bleeding.105-116 For example, Davenport105 found that a
bolus of 0.5 mg/kg of enoxaparin and 2,500 IU of
tinzaparin was sufficient to prevent clots for most
patients, although these doses are about half the
manufacturers recommended dose.
Despite their similarities, different formulations of
LMWH have varying pharmacokinetics that affect
their administration for nonstandard hemodialysis
schedules.105 For example, tinzaparin has a relatively
short half-life of 5 hours; thus, most patients need a
second bolus when they dialyze for more than 3
hours. However, enoxaparin has a long half-life of up
to 24 hours and thus may not be safe for use with daily
dialysis unless subsequent doses are decreased to
prevent accumulation.
In contrast to Europe, the use of LMWH remains
limited in the United States, where it is not approved
for use with hemodialysis and remains prohibitively
expensive.5,105 The variety of drugs in this class, each
with slightly different dosing schedules, also may
explain its low rate of use. Despite its low rate of
bleeding complications, the lack of a reversal agent
Am J Kidney Dis. 2012;60(3):473-486

further discourages its use among conservative practitioners.

Direct Thrombin Inhibitors
Argatroban and hirudin are direct thrombin inhibitors that have been used successfully to anticoagulate
the dialysis circuit in patients with HIT (Fig 1). In a
review of 253 long-term hemodialysis patients in
whom argatroban was used, only 5 cases of major
bleeding were reported.117 However, argatroban should
be avoided in patients with liver failure because it is
hepatically cleared. There also is no reversal agent for
the drug, and it is significantly more expensive than
UFH.
Hirudin, which is available in recombinant forms as
desirudin, bivalirudin, and lepirudin, is found in
leeches; it was the first anticoagulant used for hemodialysis prior to the introduction of heparin.118 A crossover study of 11 patients showed that hirudin was just
as effective as UFH in achieving adequate dialysis
(defined by clearance of plasma urea and creatinine)
with less platelet accumulation in the filter, but this
study did not track long-term bleeding events.119
However, hirudin has a number of complications.118
481

Shen and Winkelmayer

Monitoring anticoagulation by aPTTs can be inaccurate because the dose-response curve is not linear; at
higher concentrations of hirudin, the aPTT underestimates the extent of anticoagulation. It also is highly
immunogenic; up to 74% of patients develop antibodies to the drug, which can increase the drugs half-life.
This can easily lead to overanticoagulation, especially
in dialysis patients, for whom the typical half-life is
already 35 hours because the drug primarily is renally
cleared. Similar to argatroban, there is no reversal
agent, and it is not as economical as UFH.
Heparinoids
Danaparoid is a heparin derivative, but releases less
PF4 than UFH or LMWH and thus has gained use in
the HIT population (Fig 1). A review of 122 patients
who had a contraindication to heparin use found 14
nonfatal bleeding events and 8 instances of dialysis
circuit clotting.120 Danaparoid currently is not available in the United States. Concern that it has proven
cross-reactivity with HIT antibodies in a small percentage of patients has slowed its adoption of use in other
countries.
Fondaparinux is a synthetic pentasaccharide that
binds antithrombin. A small crossover study of 12
patients showed that fondaparinux could sufficiently
anticoagulate the dialysis circuit, although less effectively than UFH, as measured by anti-Xa level and a
visual scale of clotting of the circuit.121 Half the
patients also experienced minor bleeding problems,
perhaps because the half-life of the drug is increased
in patients with kidney failure. Overall, this relatively new drug is at best appropriate only in
patients who may need constant anticoagulation,
not just with dialysis.
Regional Citrate Anticoagulation
Citrate is a compound that binds calcium, an essential component of the coagulation cascade (Fig 1).
Citrate anticoagulation involves infusing citrate into
the circuit before the blood enters the machine and
then reversing its effect by adding calcium back to the
circuit before it returns to the patient; this theoretically provides regional anticoagulation. Postcircuit
calcium replacement also prevents the other complications of acute hypocalcemia, which include tetany,
seizures, papilledema, arrhythmia, hypotension, and
heart failure. Although used more commonly in continuous modes of hemodialysis, citrate anticoagulation also has been studied in long-term intermittent
hemodialysis. A prospective 2-year trial of 59 patients
found that it was safe; only 0.2% experienced adverse
effects.122 There were no instances of hypernatremia,
alkalosis, or hypocalcemia, the most common metabolic complications of the process. However, cost
482

remains a barrier to widespread use. Also, calcium

levels must be drawn multiple times during the dialysis session for proper titration of the calcium replacement fluid, which also increases technician labor.
Anticoagulant-Free Dialysis
In cases in which patients have both a contraindication to heparin and an increased risk of bleeding,
saline solution is used in place of anticoagulants.
Saline boluses of 100-200 mL are injected every
15-60 minutes. Although there is no increased risk of
bleeding with saline, the rates of clotting that required
a change of the dialyzer range from 3%-10% of
sessions, whereas no dialyzers needed to be changed
when heparin was used.123-127 The extra volume of
saline also increases the ultrafiltration rate, which can
lead to hypotension and increased clotting. Finally,
the increased technician labor and dialyzer use can
double the cost of dialysis, making it a poor choice for
long-term outpatient hemodialysis.
Peritoneal Dialysis
Finally, peritoneal dialysis is a sometimes overlooked alternative to heparin-free hemodialysis. The
costs are lower, the hypotension that complicates
anticoagulant-free hemodialysis generally is avoided,
and patients can avoid all heparin by using alternative
solutions for their catheter locks. Some patients receive hemodialysis because they have a contraindication to peritoneal dialysis, but in others, it may offer a
reasonable treatment alternative.

CONCLUSION
UFH is the most common anticoagulant used for
long-term hemodialysis, although the dosage has not
been standardized in the United States. Its side effects
include bleeding, HIT, hypertriglyceridemia, anaphylaxis, and possibly bone mineral disease, hyperkalemia, and catheter-associated sepsis.
Alternatives include anticoagulation with LMWH,
which is easier to dose, but prohibitively expensive in
certain countries. Patients with a history of heparin
allergy or HIT can receive direct thrombin inhibitors
or heparinoids. However, the prolonged half-life and
lack of reversal agents for these anticoagulants make
them poor choices for patients at high risk of hemorrhage. Both regional citrate anticoagulation and anticoagulant-free hemodialysis are safe alternatives for
patients who must avoid systemic anticoagulation; we
favor the latter because it is simpler to set up and
monitor, although it results in high rates of clotting.
Finally, peritoneal dialysis also should be considered
because it is less expensive and requires no anticoagulation, although it can be contraindicated for other
social and medical reasons.
Am J Kidney Dis. 2012;60(3):473-486

Heparin During Maintenance Hemodialysis

In general, with appropriate use and monitoring,

UFH is a relatively safe and low-cost choice for
anticoagulation. Still, these conclusions are drawn
from relatively low levels of evidence based on
varying dosages of heparin. Large-scale studies (eg,
cluster-randomized trials) should be performed on
contemporary cohorts to confirm the relative safety of
different anticoagulation protocols to identify the therapeutic range at which risks and benefits are optimally
balanced.

CASE REVIEW
The patients recent life-threatening GI bleed was a
relative contraindication to systemic anticoagulation
during hemodialysis. His major abdominal surgery
made him a poor candidate for peritoneal dialysis, and
his dialysis unit was not familiar with regional citrate
anticoagulation. Thus, he initially resumed long-term
hemodialysis anticoagulant free. However, clotting of
the dialyzer required the nurses to change the circuit
at least once per session. Because the patient had
neither clinical nor laboratory characteristics suggestive of HIT, heparin was not contraindicated. Consequently, 2 weeks after discharge, he was switched to a
single loading bolus of 2,000 IU of UFH with no
maintenance infusion. He had no further clotting of
the dialysis circuit or bleeding complications on this
dose.
ACKNOWLEDGEMENTS
We gratefully acknowledge Dr Kristin Sainanis comments on
earlier drafts of this manuscript.
Support: Dr Shen is a 2010 American Kidney Fund-Amgen
Clinical Scientist in Nephrology Fellow.
Financial Disclosure: The authors declare that they have no
other relevant financial interests.

REFERENCES
1. US Renal Data System. USRDS 2010 Annual Data Report:
Atlas of Chronic Kidney Disease and End-Stage Renal Disease in
the United States. Am J Kidney Dis. 2011;57(1)(suppl 1):e1-e526.
2. Cameron JS. Practical haemodialysis began with cellophane
and heparin: the crucial role of William Thalhimer (1884-1961).
Nephrol Dial Transplant. 2000;15(7):1086-1091.
3. Fellner SK, Purkerson ML. Gordon Murray: heparin, hemodialysis and hubris. Am J Nephrol. 2002;22(2-3):271-277.
4. Brunet P, Simon N, Opris A, et al. Pharmacodynamics of
unfractionated heparin during and after a hemodialysis session.
Am J Kidney Dis. 2008;51(5):789-795.
5. Cronin RE, Reilly RF. Unfractionated heparin for hemodialysis: still the best option. Semin Dial. 2010;23(5):510-515.
6. Schmitt Y, Schneider H. Low-molecular-weight heparin
(LMWH): influence on blood lipids in patients on chronic haemodialysis. Nephrol Dial Transplant. 1993;8(5):438-442.
7. Ethier J, Bragg-Gresham JL, Piera L, et al. Aspirin prescription and outcomes in hemodialysis patients: the Dialysis Outcomes
and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2007;50(4):
602-611.
Am J Kidney Dis. 2012;60(3):473-486

8. Saran R, Dykstra DM, Wolfe RA, Gillespie B, Held PJ,

Young EW. Association between vascular access failure and the
use of specific drugs: the Dialysis Outcomes and Practice Patterns
Study (DOPPS). Am J Kidney Dis. 2002;40(6):1255-1263.
9. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Anticoagulant and antiplatelet usage associates with mortality among hemodialysis patients. J Am Soc Nephrol. 2009;20(4):872-881.
10. Holden RM, Harman GJ, Wang M, Holland D, Day AG.
Major bleeding in hemodialysis patients. Clin J Am Soc Nephrol.
2008;3(1):105-110.
11. Reinecke H, Brand E, Mesters R, et al. Dilemmas in the
management of atrial fibrillation in chronic kidney disease. J Am
Soc Nephrol. 2009;20(4):705-711.
12. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria
and glomerular filtration rate on risk of thromboembolism in atrial
fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Circulation. 2009;119(10):1363-1369.
13. Phelan PJ, OKelly P, Holian J, et al. Warfarin use in
hemodialysis patients: what is the risk? Clin Nephrol. 2011;75(3):
204-211.
14. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation
in hemodialysis patients: clinical features and associations with
anticoagulant therapy. Kidney Int. 2010;77(12):1098-1106.
15. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK.
Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol.
2011;6(11):2662-2668.
16. Blake PG, Daugirdas JT, Ing TS, eds. Handbook of Dialysis. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2007.
17. Weitz JI. Antiplatelet, anticoagulant, and fibrinolytic drugs. In:
Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo
J, eds. Harrisons Principles of Internal Medicine. 18th ed. New York:
McGraw-Hill; 2012. http://www.accessmedicine.com/content.
aspx?aID9101027. Accessed April 16, 2012.
18. Chanard J, Lavaud S, Maheut H, Kazes I, Vitry F, Rieu P.
The clinical evaluation of low-dose heparin in haemodialysis: a
prospective study using the heparin-coated AN69 ST membrane.
Nephrol Dial Transplant. 2008;23(6):2003-2009.
19. Lee KB, Kim B, Lee YH, et al. Hemodialysis using heparinbound Hemophan in patients at risk of bleeding. Nephron Clin
Pract. 2004;97(1):c5-c10.
20. Gunnarsson B, Asaba H, Dawidson S, Wilhelmsson S,
Bergstrom J. The effects of three different heparin regimes on
heparin concentrations in plasma and fibrin formation in dialyzers.
Clin Nephrol. 1981;15(3):135-142.
21. Norton J, Spiezio R, LaManna L, DeLorme B. Varying
heparin requirements in hemodialysis patients receiving erythropoietin. ANNA J. 1992;19(4):367-372, 408; discussion 409.
22. Veys N, Vanholder R, De Cuyper K, Ringoir S. Influence of
erythropoietin on dialyzer reuse, heparin need, and urea kinetics in
maintenance hemodialysis patients. Am J Kidney Dis. 1994;
23(1):52-59.
23. Spinowitz BS, Arslanian J, Charytan C, Golden RA, Rascoff J, Galler M. Impact of epoetin beta on dialyzer clearance and
heparin requirements. Am J Kidney Dis. 1991;18(6):668-673.
24. Aquino RS, Pereira MS, Vairo BC, et al. Heparins from
porcine and bovine intestinal mucosa: are they similar drugs?
Thromb Haemost. 2010;103(5):1005-1015.
25. Krauskopf L. FDA issues plan to avoid heparin contamination. Reuters.com. 2012. http://www.reuters.com/article/2012/02/
10/us-fda-heparin-idUSTRE8190RB20120210. Accessed February 13, 2012.
26. Blossom DB, Kallen AJ, Patel PR, et al. Outbreak of
adverse reactions associated with contaminated heparin. N Engl
J Med. 2008;359(25):2674-2684.
483

Shen and Winkelmayer

27. Dooren JC. Suppliers linked to impure heparin. Wall Street J.
2012. http://online.wsj.com/article/SB100014240529702039608
04577239624228625522.html. Accessed March 23, 2012.
28. Davenport A. Optimization of heparin anticoagulation for
hemodialysis. Hemodial Int. 2011;15(suppl 1):S43-S48.
29. Ouseph R, Ward RA. Anticoagulation for intermittent hemodialysis. Semin Dial. 2000;13(3):181-187.
30. Mingardi G, Perico N, Pusineri F, et al. Heparin for hemodialysis: practical guidelines for administration and monitoring. Int J
Artif Organs. 1984;7(5):269-274.
31. Wilhelmsson S, Lins LE. Heparin elimination and hemostasis in hemodialysis. Clin Nephrol. 1984;22(6):303-306.
32. Ward RA, Farrell PC. Precise anticoagulation for routine
hemodialysis using nomograms. Trans Am Soc Artif Intern Organs. 1978;24:439-442.
33. Low CL, Bailie G, Morgan S, Eisele G. Effect of a sliding
scale protocol for heparin on the ability to maintain whole blood
activated partial thromboplastin times within a desired range in
hemodialysis patients. Clin Nephrol. 1996;45(2):120-124.
34. Kandrotas RJ, Gal P, Douglas JB, Deterding J. Pharmacokinetics and pharmacodynamics of heparin during hemodialysis:
interpatient and intrapatient variability. Pharmacotherapy. 1990;
10(5):349-355.
35. Jannett TC, Wise MG, Shanklin NH, Sanders PW. Adaptive
control of anticoagulation during hemodialysis. Kidney Int. 1994;
45(3):912-915.
36. Ouseph R, Brier ME, Ward RA. Improved dialyzer reuse
after use of a population pharmacodynamic model to determine
heparin doses. Am J Kidney Dis. 2000;35(1):89-94.
37. Ehrmeyer SS, Laessig RH. Regulatory compliance for pointof-care testing: 2009 United States perspective. Clin Lab Med.
2009;29(3):463-478.
38. European Best Practice Guidelines Working Group. Section
V. Chronic intermittent haemodialysis and prevention of clotting in
the extracorporal system. Nephrol Dial Transplant. 2002;17(suppl
7):63-71.
39. Gordon LA, Perkins HA, Richards V. Studies in regional
heparinization. I. The use of simultaneous neutralization with
protamine; preliminary studies. N Engl J Med. 1956;255(22):10251029.
40. Hampers CL, Balufox MD, Merrill JP. Anticoagulation
rebound after hemodialysis. N Engl J Med. 1966;275(14):776-778.
41. Blaufox MD, Hampers CL, Merrill JP. Rebound anticoagulation occurring after regional heparinization for hemodialysis.
Trans Am Soc Artif Intern Organs. 1966;12:207-209.
42. Lavaud S, Paris B, Maheut H, et al. Assessment of the
heparin-binding AN69 ST hemodialysis membrane: II. Clinical
studies without heparin administration. ASAIO J. 2005;51(4):348351.
43. Wright MJ, Woodrow G, Umpleby S, Hull S, Brownjohn
AM, Turney JH. Low thrombogenicity of polyethylene glycolgrafted cellulose membranes does not influence heparin requirements in hemodialysis. Am J Kidney Dis. 1999;34(1):36-42.
44. Evenepoel P. Heparin-coated hemodialyzersthe holy grail
for patients at risk of bleeding? Nephron Clin Pract. 2004;97(1):
c1-c2.
45. Swartz RD, Port FK. Preventing hemorrhage in high-risk
hemodialysis: regional versus low-dose heparin. Kidney Int. 1979;
16(4):513-518.
46. Swartz RD. Hemorrhage during high-risk hemodialysis
using controlled heparinization. Nephron. 1981;28(2):65-69.
47. Wasse H, Gillen DL, Ball AM, et al. Risk factors for upper
gastrointestinal bleeding among end-stage renal disease patients.
Kidney Int. 2003;64(4):1455-1461.
484

48. Chachati A, Godon JP. Effect of haemodialysis on upper

gastrointestinal tract pathology in patients with chronic renal
failure. Nephrol Dial Transplant. 1987;1(4):233-237.
49. Yang JY, Lee TC, Montez-Rath ME, et al. Trends in acute
nonvariceal upper gastrointestinal bleeding in dialysis patients.
J Am Soc Nephrol. 2012;23(3):495-506.
50. Baroni CD. The pathobiography and death of Wolfgang
Amadeus Mozart: from legend to reality. Hum Pathol. 1997;28(5):
519-521.
51. Seliger SL, Gillen DL, Longstreth WT Jr, Kestenbaum B,
Stehman-Breen CO. Elevated risk of stroke among patients with
end-stage renal disease. Kidney Int. 2003;64(2):603-609.
52. Kawamura M, Fijimoto S, Hisanaga S, Yamamoto Y, Eto T.
Incidence, outcome, and risk factors of cerebrovascular events in
patients undergoing maintenance hemodialysis. Am J Kidney Dis.
1998;31(6):991-996.
53. Iseki K, Kinjo K, Kimura Y, Osawa A, Fukiyama K.
Evidence for high risk of cerebral hemorrhage in chronic dialysis
patients. Kidney Int. 1993;44(5):1086-1090.
54. Bhasin HK, Dana CL. Spontaneous retroperitoneal hemorrhage in chronically hemodialyzed patients. Nephron. 1978;22(46):322-327.
55. Vanichayakornkul S, Cioffi RF, Harper E, OConnell JM,
Shalhoub RJ. Spontaneous retroperitoneal hematoma. A complication of hemodialysis. JAMA. 1974;230(8):1164-1165.
56. De Santo NG, Capodicasa G, Perna N, De Pascale C,
Giordano C. Haematoma of rectus abdominis associated with
dialysis. Br Med J. 1972;3(5821):281-282.
57. Milutinovich J, Follette WC, Scribner BH. Spontaneous
retroperitoneal bleeding in patients on chronic hemodialysis. Ann
Intern Med. 1977;86(2):189-192.
58. Hayashi H, Kurata Y, Imanaga Y, Goya K, Oshima K.
Vitrectomy for diabetic retinopathy in patients undergoing hemodialysis for associated end-stage renal failure. Retina. 1998;18(2):156159.
59. Slusher MM, Hamilton RW. Spontaneous hyphema during
hemodialysis [letter]. N Engl J Med. 1975;293(11):561.
60. Galen MA, Steinberg SM, Lowrie EG, Lazarus JM, Hampers CL, Merrill JP. Hemorrhagic pleural effusion in patients
undergoing chronic hemodialysis. Ann Intern Med. 1975;82(3):359361.
61. Alfrey AC, Goss JE, Ogden DA, Vogel JH, Holmes JH.
Uremic hemopericardium. Am J Med. 1968;45(3):391-400.
62. Davenport A. Antibodies to heparin-platelet factor 4 complex: pathogenesis, epidemiology, and management of heparininduced thrombocytopenia in hemodialysis. Am J Kidney Dis.
2009;54(2):361-374.
63. Chong BH. Heparin-induced thrombocytopenia. Blood Rev.
1988;2(2):108-114.
64. Davenport A. Heparin-induced thrombocytopenia during
renal replacement therapy. Hemodial Int. 2004;8(3):295-303.
65. Aird WC, Mark EJ. Case records of the Massachusetts
General Hospital. Weekly clinicopathological exercises. Case 15200. A 53-year-old man with a myocardial infarct and thromboses
after coronary-artery bypass grafting. N Engl J Med. 2002;346(20):
1562-1570.
66. King DJ, Kelton JG. Heparin-associated thrombocytopenia.
Ann Intern Med. 1984;100(4):535-540.
67. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition). Chest. 2008;133(6)(suppl):340S-380S.
68. Hutchison CA, Dasgupta I. National survey of heparininduced thrombocytopenia in the haemodialysis population of the
UK population. Nephrol Dial Transplant. 2007;22(6):1680-1684.
Am J Kidney Dis. 2012;60(3):473-486

Heparin During Maintenance Hemodialysis

69. Yamamoto S, Koide M, Matsuo M, et al. Heparin-induced
thrombocytopenia in hemodialysis patients. Am J Kidney Dis.
1996;28(1):82-85.
70. Chang JJ, Parikh CR. When heparin causes thrombosis:
significance, recognition, and management of heparin-induced
thrombocytopenia in dialysis patients. Semin Dial. 2006;19(4):297304.
71. Matsuo T, Kobayashi H, Matsuo M, et al. Frequency of
anti-heparin-PF4 complex antibodies (HIT antibodies) in uremic
patients on chronic intermittent hemodialysis. Pathophysiol Haemost Thromb. 2006;35(6):445-450.
72. Mureebe L, Coats RD, Silliman WR, Shuster TA, Nichols
WK, Silver D. Heparin-associated antiplatelet antibodies increase
morbidity and mortality in hemodialysis patients. Surgery. 2004;
136(4):848-853.
73. Carrozza P, Gabutti L, Gilliet F, Marone C. Heparininduced systemic inflammatory response syndrome with progressive skin necrosis in haemodialysis. Nephrol Dial Transplant.
1997;12(11):2424-2427.
74. Leblanc M, Roy LF, Legault L, Dufresne LR, Morin C,
Thuot C. Severe skin necrosis associated with heparin in hemodialysis. Nephron. 1994;68(1):133-137.
75. Popov D, Zarrabi MH, Foda H, Graber M. Pseudopulmonary embolism: acute respiratory distress in the syndrome of
heparin-induced thrombocytopenia. Am J Kidney Dis. 1997;29(3):
449-452.
76. Davenport A. Sudden collapse during haemodialysis due to
immune-mediated heparin-induced thrombocytopaenia. Nephrol
Dial Transplant. 2006;21(6):1721-1724.
77. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep. 2003;
2(2):148-157.
78. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy. Chest.
2004;126(3)(suppl):311S-337S.
79. Pena de la Vega L, Miller RS, Benda MM, et al. Association
of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a population-based study. Mayo Clin Proc. 2005;
80(8):995-1000.
80. Nakamoto H, Shimada Y, Kanno T, Wanaka K, Matsuo T,
Suzuki H. Role of platelet factor 4-heparin complex antibody (HIT
antibody) in the pathogenesis of thrombotic episodes in patients on
hemodialysis. Hemodial Int. 2005;9(suppl 1):S2-S7.
81. Carrier M, Rodger MA, Fergusson D, et al. Increased mortality
in hemodialysis patients having specific antibodies to the platelet
factor 4-heparin complex. Kidney Int. 2008;73(2):213-219.
82. Krane V, Berger M, Lilienthal J, Winkler K, Schambeck C,
Wanner C. Antibodies to platelet factor 4-heparin complex and
outcome in hemodialysis patients with diabetes. Clin J Am Soc
Nephrol. 2010;5(5):874-881.
83. Carrier M, Knoll GA, Kovacs MJ, Moore JC, Fergusson D,
Rodger MA. The prevalence of antibodies to the platelet factor
4-heparin complex and association with access thrombosis in patients
on chronic hemodialysis. Thromb Res. 2007;120(2):215-220.
84. Nasstrom B, Olivecrona G, Olivecrona T, Stegmayr BG.
Lipoprotein lipase during heparin infusion: lower activity in hemodialysis patients. Scand J Clin Lab Invest. 2003;63(1):45-53.
85. Nasstrom B, Stegmayr B, Olivecrona G, Olivecrona T.
Lipoprotein lipase in hemodialysis patients: indications that low
molecular weight heparin depletes functional stores, despite low
plasma levels of the enzyme. BMC Nephrol. 2004;5:17.
86. Elisaf MS, Germanos NP, Bairaktari HT, Pappas MB,
Koulouridis EI, Siamopoulos KC. Effects of conventional vs.
low-molecular-weight heparin on lipid profile in hemodialysis
patients. Am J Nephrol. 1997;17(2):153-157.
Am J Kidney Dis. 2012;60(3):473-486

87. Wiemer J, Winkler K, Baumstark M, Marz W, Scherberich

JE. Influence of low molecular weight heparin compared to conventional heparin for anticoagulation during haemodialysis on low
density lipoprotein subclasses. Nephrol Dial Transplant. 2002;
17(12):2231-2238.
88. Yang C, Wu T, Huang C. Low molecular weight heparin
reduces triglyceride, VLDL and cholesterol/HDL levels in hyperlipidemic diabetic patients on hemodialysis. Am J Nephrol. 1998;
18(5):384-390.
89. Deuber HJ, Schulz W. Reduced lipid concentrations during
four years of dialysis with low molecular weight heparin. Kidney
Int. 1991;40(3):496-500.
90. Kronenberg F, Konig P, Lhotta K, Steinmetz A, Dieplinger
H. Low molecular weight heparin does not necessarily reduce
lipids and lipoproteins in hemodialysis patients. Clin Nephrol.
1995;43(6):399-404.
91. Kronenberg F, Konig P, Neyer U, et al. Influence of various
heparin preparations on lipoproteins in hemodialysis patients: a
multicentre study. Thromb Haemost. 1995;74(4):1025-1028.
92. Hottelart C, Achard JM, Moriniere P, Zoghbi F, Dieval J,
Fournier A. Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of low molecular weight and unfractionated heparin. Artif Organs. 1998;22(7):614-617.
93. Bottio T, Pittarello G, Bonato R, Fagiolo U, Gerosa G.
Life-threatening anaphylactic shock caused by porcine heparin
intravenous infusion during mitral valve repair. J Thorac Cardiovasc Surg. 2003;126(4):1194-1195.
94. Harada A, Tatsuno K, Kikuchi T, et al. Use of bovine lung
heparin to obviate anaphylactic shock caused by porcine gut
heparin. Ann Thorac Surg. 1990;49(5):826-827.
95. Schulman S, Hellgren-Wangdahl M. Pregnancy, heparin
and osteoporosis. Thromb Haemost. 2002;87(2):180-181.
96. Binici DN, Gunes N. Risk factors leading to reduced bone
mineral density in hemodialysis patients with metabolic syndrome.
Ren Fail. 2010;32(4):469-474.
97. Lai KN, Ho K, Cheung RC, et al. Effect of low molecular
weight heparin on bone metabolism and hyperlipidemia in patients
on maintenance hemodialysis. Int J Artif Organs. 2001;24(7):447455.
98. Edes TE, Sunderrajan EV. Heparin-induced hyperkalemia.
Arch Intern Med. 1985;145(6):1070-1072.
99. Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB. Is
systemic heparin a risk factor for catheter-related sepsis in dialysis
patients? An evaluation of various biofilm and traditional risk
factors. Nephron Clin Pract. 2007;107(4):c128-c132.
100. Shanks RM, Donegan NP, Graber ML, et al. Heparin
stimulates Staphylococcus aureus biofilm formation. Infect Immun. 2005;73(8):4596-4606.
101. Hetzel GR, Sucker C. The heparins: all a nephrologist
should know. Nephrol Dial Transplant. 2005;20(10):2036-2042.
102. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced
thrombocytopenia in patients treated with low-molecular-weight
heparin or unfractionated heparin. N Engl J Med. 1995;332(20):
1330-1335.
103. Lim W, Cook DJ, Crowther MA. Safety and efficacy of
low molecular weight heparins for hemodialysis in patients with
end-stage renal failure: a meta-analysis of randomized trials. J Am
Soc Nephrol. 2004;15(12):3192-3206.
104. Crowther MA, Berry LR, Monagle PT, Chan AK. Mechanisms responsible for the failure of protamine to inactivate lowmolecular-weight heparin. Br J Haematol. 2002;116(1):178-186.
105. Davenport A. Review article: low-molecular-weight heparin as an alternative anticoagulant to unfractionated heparin for
routine outpatient haemodialysis treatments. Nephrology (Carlton). 2009;14(5):455-461.
485

Shen and Winkelmayer

106. Borm JJ, Krediet R, Sturk A, ten Cate JW. Heparin versus
low molecular weight heparin K 2165 in chronic hemodialysis
patients: a randomized cross-over study. Haemostasis. 1986;
16(suppl 2):59-68.
107. Schrader J, Stibbe W, Armstrong VW, et al. Comparison of
low molecular weight heparin to standard heparin in hemodialysis/
hemofiltration. Kidney Int. 1988;33(4):890-896.
108. Anastassiades E, Lane DA, Ireland H, Flynn A, Curtis JR.
A low molecular weight heparin (fragmin) for routine hemodialysis: a crossover trial comparing three dose regimens with a standard regimen of commercial unfractionated heparin. Clin Nephrol.
1989;32(6):290-296.
109. Nurmohamed MT, ten Cate J, Stevens P, Hoek JA, Lins
RL, ten Cate JW. Long-term efficacy and safety of a low molecular
weight heparin in chronic hemodialysis patients. A comparison
with standard heparin. ASAIO Trans. 1991;37(3):M459-M461.
110. Ryan KE, Lane DA, Flynn A, Shepperd J, Ireland HA, Curtis
JR. Dose finding study of a low molecular weight heparin, Innohep, in
haemodialysis. Thromb Haemost. 1991;66(3):277-282.
111. Harenberg J, Haaf B, Dempfle CE, Stehle G, Heene DL.
Monitoring of heparins in haemodialysis using an anti-factor-Xaspecific whole-blood clotting assay. Nephrol Dial Transplant.
1995;10(2):217-222.
112. Moia M, Graziani G, Tenconi PM, Martinelli I, Ponticelli
C. Rationale for the use of a low molecular weight heparin during
hemodialysis with polysulphone membrane in uremic patients.
Ann Ital Med Int. 1997;12(2):67-71.
113. Saltissi D, Morgan C, Westhuyzen J, Healy H. Comparison of low-molecular-weight heparin (enoxaparin sodium) and
standard unfractionated heparin for haemodialysis anticoagulation.
Nephrol Dial Transplant. 1999;14(11):2698-2703.
114. Stefoni S, Cianciolo G, Donati G, et al. Standard heparin
versus low-molecular-weight heparin. A medium-term comparison
in hemodialysis. Nephron. 2002;92(3):589-600.
115. Lord H, Jean N, Dumont M, Kassis J, Leblanc M. Comparison between tinzaparin and standard heparin for chronic hemodialysis in a Canadian center. Am J Nephrol. 2002;22(1):58-66.

486

116. Leu JG, Chiang SS, Lin SM, Pai JK, Jiang WW. Low
molecular weight heparin in hemodialysis patients with a bleeding
tendency. Nephron. 2000;86(4):499-501.
117. Hursting MJ, Murray PT. Argatroban anticoagulation in
renal dysfunction: a literature analysis. Nephron Clin Pract. 2008;
109(2):c80-c94.
118. Greinacher A, Warkentin TE. The direct thrombin inhibitor hirudin. Thromb Haemost. 2008;99(5):819-829.
119. van Wyk V, Badenhorst PN, Luus HG, Kotze HF. A
comparison between the use of recombinant hirudin and heparin
during hemodialysis. Kidney Int. 1995;48(4):1338-1343.
120. Magnani HN. A review of 122 published outcomes of
danaparoid anticoagulation for intermittent haemodialysis. Thromb
Res. 2010;125(4):e171-e176.
121. Kalicki RM, Aregger F, Alberio L, Lammle B, Frey FJ,
Uehlinger DE. Use of the pentasaccharide fondaparinux as an
anticoagulant during haemodialysis. Thromb Haemost. 2007;98(6):
1200-1207.
122. Apsner R, Buchmayer H, Gruber D, Sunder-Plassmann G.
Citrate for long-term hemodialysis: prospective study of 1,009
consecutive high-flux treatments in 59 patients. Am J Kidney Dis.
2005;45(3):557-564.
123. Caruana RJ, Raja RM, Bush JV, Kramer MS, Goldstein SJ.
Heparin free dialysis: comparative data and results in high risk
patients. Kidney Int. 1987;31(6):1351-1355.
124. Keller F, Seemann J, Preuschof L, Offermann G. Risk
factors of system clotting in heparin-free haemodialysis. Nephrol
Dial Transplant. 1990;5(9):802-807.
125. Casati S, Moia M, Graziani G, et al. Hemodialysis without
anticoagulants: efficiency and hemostatic aspects. Clin Nephrol.
1984;21(2):102-105.
126. Preuschof L, Keller F, Seemann J, Offermann G. Heparinfree hemodialysis with prophylactic change of dialyser and blood
lines. Int J Artif Organs. 1988;11(4):255-258.
127. Sanders PW, Taylor H, Curtis JJ. Hemodialysis without
anticoagulation. Am J Kidney Dis. 1985;5(1):32-35.

Am J Kidney Dis. 2012;60(3):473-486